Controlled Burning: Towards the rational redesign of O2 and nonheme Fe(II) enzymes

Johannes Niederhauser

Research output: Contribution to conference(Old data) Lecture or Presentation


Selective oxygenations of non-activated carbon atoms by O2 are a major target in green chemistry, as they are often inaccessible by abiotic synthetic means. Mononuclear O2 and nonheme iron dependent dioxygenases (MNHD) constitute a very versatile group of enzymes which are capable of highly selective oxidative transformations that complement P450 dependent catalysis. MNHDs generally share a common metal binding motif consisting of two histidines and one carboxylate moiety that ligate a Fe(II) cofactor. Yet, they display an impressive diversity, which is brought about by the respective protein environment. Understanding the mechanisms by which the interplay of metal center and protein structure achieve stereo- and regio- selective transformations is a prerequisite for the rational design of novel, O2 dependent biocatalysis.

Here we discuss recent advances in the computer assisted tailoring of MNHDs.
One interesting enzyme in this respect is the (S)-4-hydroxyphenylpyruvate dioxygenase (HMS) which catalyzes a multi-step process that has the ability to oxidize nonactivated hydrocarbon moieties. Recent studies showed combining knowledge of structural information together with an in depth understanding of the enzyme mechanism and molecular dynamics simulations (MD) have the potential to enable tailoring of alternative and still highly specific activities of MNHDs. Several steps of calibration combining computional analysis in silico and mutational analysis in vitro led to inversion of enantioselectivity.

The principles and methods derived from redesigning HMS are subsequently applied to other interesting enzymes which could enable new routes to fine chemicals and pharmaceutical building blocks currently unavailable through single enzyme reactions.

We discuss potentials and pitfalls on our way towards a computational methodology for the rational design of O2 and nonheme metal dependent biological catalysts.
Original languageEnglish
Publication statusPublished - Dec 2015
EventPacifichem 2015 - Honolulu, Hawaii, U.S.A.
Duration: 15 Dec 201520 Dec 2015


ConferencePacifichem 2015
CityHonolulu, Hawaii, U.S.A.

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